At least as far back as the early 1970s, it was found that dithiocarbamates and their dimers (e.g., disulfiram) are clinically useful compounds of relatively low toxicity toward mammals. Various sulfur-containing compounds including sodium diethyldithiocarbamate (NaDDTC) have been suggested as immunostimulant medicines. See U.S. Pat. No. 4,148,885 (Renoux et al.), issued Apr. 10, 1979. Also, dithiocarbamates or their dimers have been used to inhibit the undesirable side effects of platinum compounds such as the square planer platinum (II) complexes used as antineoplastic agents. See U.S. Pat. Nos. 4,426,372 (Jan. 17, 1984), 4,594,238 (Jun. 10, 1986), and 4,581,224 (Apr.8, 1986), all issued to R. F. Borch. The platinum compounds useful as antineoplastic agents are not limited to platinum (II) compounds, because it has been found that platinum (IV) compounds can be administered in much the same manner as platinum (II) compounds, apparently because these six-ligand complexes break down in vivo to square planar complexes of the platinum (II) type.
The Borch method of, for example, U.S. Pat. No. 4,426,372, has been shown to be effective in clinical trials. That is, this method substantially reduces the side effects of platinum-containing drugs. These side effects include both kidney toxicity and bone marrow toxicity. For 5 mg/kg of intravenously administered platinum compound in mice, the amount of dithiocarbamic "rescue agent" is likely to be in the range of 100 mg/kg to 400 mg/kg (intravenously) and can range as high as 750 mg/kg (intraperitoneally), also in mice. A dosage of less than 50 mg/kg of body weight of dithiocarbamate is not likely to be fully effective in providing relief from or prevention of kidney damage.
Although pharmaceutically acceptable dithiocarbamic compounds such as sodium diethyldithiocarbamate (NaDDTC) and disulfiram have relatively high LD.sub.50 values and are not considered highly toxic to mammals, there are scattered reports in the literature regarding strange behavior exhibited by rats or mice injected with NaDDTC. The true import of this literature became fully apparent during clinical trials of NaDDTC as a "rescue agent"i.e., as an agent for the reduction of side effects from the administration of platinum compounds. These clinical trials demonstrated that human patients given dosages of NaDDTC effective for "rescue" purposes (e.g., dosages on the order of 50-150 mg/kg of body weight) experienced extremely unpleasant effects which caused them to feel panic and discomfort. It was necessary to develop a technique of administration of the NaDDTC whereby the patient is sedated prior to receiving the dithiocarbamate.
All available evidence indicates that the panic reaction to dithiocarbamates resulting from dosages of, for example, 50-150 mg/kg is not the result of any life-threatening process occurring in the body of the patient, nor is there any evidence of permanent or chronic effects or damage resulting from NaDDTC administration. After the course of dithiocarbamate administration has been completed, patients returned to normal and no sequellae of the panic reaction are observed. Moreover, it presently appears that some hydroxy-substituted analogs of NaDDTC may be even less toxic than NaDDTC itself. Nevertheless, further improvement in the treatment of toxic side effects of useful cytotoxic compounds is desirable.
As noted previously, much less is known about treatments for bone marrow toxicity. Some anti-cancer drugs, both platinum-containing and platinum-free, can seriously damage the blood-forming function of the bone marrow--an effect sometimes referred to as myelosuppression. Among the drugs causing significant myelosuppression effects are the toxin-derivative, etoposide, certain heavy metal complexes, as well as cytotoxic antibiotics and antibiotic derivatives, antimetabolites, alkaloid-type anti-tumor agents, and alkylating agents. Although dithiocarbamates have been shown to effectively inhibit the myelosuppression caused by platinum-containing antineoplastic drugs, such as carboplatin or cisplatin, little is known about their interaction with platinum-free antineoplastic drugs.
Therefore, a need exists to counteract or prevent the myelosuppression caused by platinum-free cytotoxic, antineoplastic drugs, particularly myelosuppression caused by etoposide.